In the continuous culture of human lymphocytes it has been previously demonstrated that there is a progressive loss of in vitro stimulating capacity (L.D. components) in undirectional mixed lymphocyte culture (MLC) with a retention of HL-A typing specificities (S.D. components). Phytohemagglutinin (PHA) and Concanavalin A (Con A) accelerate this modulation from 4-6 weeks to 7 days. These findings have now been extended to transplantation experiments in inbred mice. DBA/2 strain recipients of Balb/c strain skin allografts were pretreated by IP injection of 45 x 10 to the 6th power splenic lymphocytes of the Balb/c donors, 2 strains with non-H-2, M locus incompatibilities and strong MLC reactivity. The donor lymphocytes were either cultured without mitogens or in the presence of Con A or PHA. The variables of latency between injection and grafting, route of inoculation and duration in tissue culture were examined. The mean allograft survival time in days plus or minus S.E. was prolonged to twice that of controls, with several animals showing vigorous hair growth at 60 days. In control groups, pretreatment by IP injection with syngeneic DBA/2 mitogen cultured lymphocytes, fresh x-irradiated Balb/c cells or IV injection of the Balb/c cultured cells did not cause the same effect. Assays using the MLC demonstrated that modulation of the cell surface by culture with phytomitogens altered the responsiveness to cells so treated which correlated with enhanced skin allograft acceptance. It is proposed to investigate the mechanism of action of this phenomenon by adaptive transfer experiments and further in vitro lymphocyte culture work.